The discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) accelerated the research of molecular-targeted therapy by EGFR-tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. About 90% of EGFR mutations are clustered in exons 19 (deletion) and 21 (point mutation at codon 858) and patients with these mutations have great response to EGFR-TKIs. However, tumors that initially respond to EGFR-TKIs almost inevitably become resistant later and T790M secondary mutation in the EGFR gene and MET amplification are reported to account for the mechanism of this acquired resistance. In this review, we summarize the recent findings about EGFR mutations, amplification, alterations of other related genes and sensitivity and acquired resistance to EGFR-TKIs. We also discuss from our studies the relationship between EGFR mutations and other molecular alterations such as aberrant methylation in tumor suppressor genes (TSGs), which indicates that they are related to the mechanism of the pathogenesis of lung cancer. The accumulated important data confer further insights on translational research, providing us with the new strategies for the treatment of NSCLCs.